6-fluoro steroids and process



H ,6-FLUR0 STEROIDS AND PROCESS Barney); Magerlein, Kalamazoo, andGeorge B. Spero, William P. Schneider, and John A. Hogg, Kalamazoo TheUpjohn Compa y, tion of Michigan I No Application November 29, 1957 1 ySerial No. 699,468

t 4 Claims. (Cl. 260-39745) Kalamazoo, Mich, a corporamore particularlyconcerned .with 60:,21-diflt1010-21-d6- soxyhydroco'rtisone, 6u,21difluoro 21 desoxycortisone and 9a-halo derivatives of such compounds,and to processes for the production thereof.

7 The compounds of this invention, 6,21-difluoro- 2ldesoxyhydrocortisoneand 6,2l-difluoro-Zl-desoxycortisone, possess valuable anti-rheumatoidarthritic, anti-inflammatory and glucocorticoid activities in markeddegree. Thus, for example, 6a,2l-difluoro-Zl-desoxyhydrocortisone hasbeen found to exhibit approximately two times the glucocorticoidactivity of hydrocortisone, eight to twenty times the anti-inflammatoryactivity of hydrocortisone, and in mineralocorticoid tests toinducesodium excretion 1.35 times and water loss two times the normalrate. These compounds are useful in the treatment of inflammatoryconditions of the skin, eyes and ears of humans and of valuabledomesticanimals, as well as contact dermatitis and other allergicreactions.

Compositions containing'the compounds of the present invention can beprepared for animal or human use by incorporatingthem in any one of theseveral dosage forms suitable for such use. Administration of the novelsteroids thus can be in conventional dosage forms, such as pills,tablets, capsules, solutions, syrups or elixir-s for oral use, or inliquid forms which are adaptable to the natural'and syntheticcorticalsteroid hormones for injectableproducts. The novel compounds can also beadministered topically in the form of ointments, creams, lotions and thelike, with or without coacting antibiotics, germicides or othermaterials forming advantageous combinations therewith. As willhereinafter be described in greater detail, these compounds areadditionally useful as intermediates in the production of6,21-difluoro-9ahalo-2l-desoxyhydrocortisone and 6,21-difluoro-9a-halo-ZI-desoxycortisone. The 9a-halo derivatives are of particularnimportancebecause they possess a combination of high anti-inflammatory andglucocorticoid properties with low concomitant mineralocorticoidactivities.

The compounds of this invention can be prepared in accordance with thefollowing reactions:

' t ds cs Patentv -To wnship, Kalamazoo County, Mich., assignors towherein R is an organic radical, particularly a hydrocarbon radicalcontaining from one to ten carbon atoms, inclusive, such as methyl,ethyl, phenyl, tolyl, naphthyl, or the like, methyl being preferred.

As indicated above and described in greater detail below, the reactionsembodied in the processes charac-' each. A further object is to providea process for the production of 6,21-difluoro-2l-desoxyhydrocortisone,

6,21-difiuoro 2l-desoxycortisone andthe 9u-halo derivatives thereof. Anadditional object is to provide a process for the production of6a,2l-difluoro-Zl-desoxyhydrocortisone, 6m,21-difiuoro-2ldesoxycortisone and their 9a-halo derivatives. v

The process of the present invention comprises treating 6-fluoro-1 1 B,17 0:,21-trihydroXy-4-pregnene-3,20-dione (6-fluorohydrocortisone) (I)with an organic sulfonyl halide to obtain the corresponding 21-ester(H), a 21- alkyl or aryl sulfonate of 6-fluoro-l1fl,17a,21-trihydroxy-4-pregnene-3,20- dione, and thereafter treating the thus produced21-alkyl or aryl sulfonate with. a fiuorinating agent to obtain thecorresponding 6,21-diflllO1O-11fl,17adihydroxy-4-pregnene-3,ZO-dione(III). 6,21-difluoro product above can be oxidized to give thecorresponding 6,21 difluoro 17oz hydroxy-4-pregnene- 3,11,20-trione (V).If the ll-keto analogue of the starting material is employed, theproduct (V) is obtained without the oxidation step. Alternatively, the6-fluoro- 11p,170:,21-trihydroXy-4-pregnene-3,20-dione 21- alkyl or arylsulfonate can be reacted with an iodinating agent to produce thecorresponding 21-iodo steroid, which can be fiuorinated to yield theZI-fluoro steroid (III).

Patented June 10,. 1958 If desired, the

=The star'ting steroidsfor the compounds and process of the presentinvention. are 6-fluorohydrocortisone and fi-fluorocortisone and areprepared in accordance with the procedures of Preparations 1 through 11herein. The preferred compounds containing the l7(20)-double bond havethe cis configuration because they are convertible in higher yields inthe oxidative hydroxylation step than are the trans isomers, althoughboth are operative.

In carrying out the process of this invention, 6-fiuoro hydrocortisoneis treated with an organic sulfonyl halide such as methanesulfonylchloride, toluenesulfonyl chloride, toluenesulfon'ylbromide,,benzenesulfonyl chloride, naphthylsulfonyl chloride, or the like, themethanesulfonic acid halides, especially methanesulfonyl chloride, beingpreferred. In the preferred'embodiment of this invention, the starting.steroid is usually reacted with the alkyl or aryl sulfonyl halide insolution in a solvent such as pyridine, benzene, toluene, or the like.Where such solvents as benzene and toluene are employed, an amount of anamine base such as pyridine at least equal to the molar amount of thesultonyl halide should also be prescut to react with the halogen acidformed. Reaction of the alkyl or aryl sulfonyl halide is conductedpreferably at temperatures between minus ten and plus sixty degreescentigrade, provided that at the lower temperatures the solvent has notsolidified. Thus, for pyridine, dioxane, toluene, orithe like,temperatures in the range of zero to-tendegree centigrade can be used,while for benzene only temperatures above five degrees centigrade aresuitable because of the relatively high melting point of benzene. Thereaction 'time is usually between about thirty minutes and eight hours,after which the product, 6-fluoro-l lfl,170:,21-trihydroxy-4-pregnene-3,ZO-dione 21- alkyl or .aryl sulfonate(II), is recovered in a convenethylene glycol solution, thepreferredcombination being potassium fluoride in dimethylsulfoxide. The. reactionis advantageously conducted under continuous heating. and it proceedsgenerally for a period of about six to 24* hours, fifteen to. twentyhours usually being sufficient. The reaction mixture is then dilutedwith an organic sol vent such as methylene chloride, chloroform,benzene, and the like, and purified ina conventional manner, as, forexample, by chromatography or solvent extraction.

Alternatively, pregnene 3,2O dione 2l-alkyl or aryl sul fonate can firstbe converted to the corresponding 21-iodo compound (IV),which'is'readily convertible to the 2l-fluoro steroid. The 21-iodocompound is preparedby reacting the said 21- alkyl or aryl sulfon-atewith an alkali metal iodide, e. g., sodium, potassium or lithium iodide,in an oxygenated hydrocarbon solution such as an alk'a'none solution, e.g., acetone. A molar excess of the iodide (three to twenty molesofaiodide permole of steroid) isgenerall'y preferred forthis reaction.The reaction mixture containing the 2l-alkyl or aryl sulfonate and thealkali metal iodide in solution is heatedto reflux for a period of aboutthree minutes to'thirty minutes. The thus produced 6-fluoro=' 21-iodo-l15,17o't dihydroxy 4 pregnene-3,20-dione can then be isolatedby"evaporati'ng the solvent. For the subsequent reaction, the 2'l-iodosteroid can be used like, orit can be employed directly as a crude thenext step of the synthesis.

The 21-iodo steroid, dissolved in a solvent such as" acetonitrile,dimethylformamjide' or ethylene glycol; is.

treated with a metal fluoride such as silver fluoride, antimonyfluoride,potassium-fluoride, orthe like, acetonitrile and silver fluoride beingpreferred. The metal fluoride should be added in small quantities atintervals, and the reaction mixture should be protected from lightduring the reaction period, which usually ranges from about onehalf tosix hours. The reaction mixture is then concentrated and theproduct'extracted as in previous purification steps to yield essentiallypure 6,21 CllflllOI'O-1lfifl70ndihydroxy-4-pregnene-3,20-dione.

The foregoing reactions constitutingeither;-theprincipal or alternativeroutes can'likewise be conductedo the corresponding ll-keto analogues.

The oxidation of 6,21-diflu0ro-l1 3,17q-dihydroxy-4- pregnene-3,20dionecan be carried out' by any known method, such as, for example, byoxidizing the said 6,21- difluoro steroid in acetic acid-solutionwithchromium trioxide, using molar quantities or a slight excess, such asfrom ten to'thirty. percent excess,.orz by oxidizing with haloamide. orimide of antacid, such a's N bromoaceu amide; N-chlorosuccinimide, or Nbromosuccinimide dis solved in pyridine, dioxane,;.or' other suitable,solvents.

At the conclusion of thE'dSll'Ed-iOXldfitlOIl reactiomthe;

vents, e. g.,.methylene chloride, ether, benzene, toluene or the like,or by chromatography.

As hereinbefore indicated, the compounds of the present invention areadditionally useful as intermediates in-the production of the valuable9tZ-fluOX'O derivatives by a 9o:- 6,2l-difluoro-l 113,171X-jdihydroxy-4-pregnene-3,20 dione can-be dehydrated with-.-N-bromoacetamide and anhydrous sulfur dioxideby p'ermitting the reactionto continue until a negative acidified" potassium iodide-starch test ofthe reaction, mixtureeis obtained. Dilution with cold water results inthe-'precipi+- halogenation procedure. Thus tation of6,2-1-difluoro-17arhydroxy-4,9 1 1)-pr'egnadienee 3,20-dione, which canbe purified by; recrystallization :from

The crystalline product can then be reacted in methylenechloride-tertiary butyl alcohol solution'awitlr' perchloric acid andN-bromoacetamide'or' N*iodosuccin-.. imide to produce a reaction mixturefrompwhich 6f2ldifluoro 9a bromo 1113,1701 dihydroxy- 4 P4 preg'nene'=3,20-dione or the corresponding 6,2l difluoro-9a-iodo." compound canberecovered by precipitation w'i'th icei The latter steroids can then bereacted in acetone solution with anhy= acetone.

water and recrystallization from acetone."

drous potassium acetate at reflux temperatures-to produce 6,21 difluoro9(11) oxido 17oz hydroxy 4'-- pregnene-3,20-dione, ,whichis recoverablefrom 'the 'reactionmixture by chromatography and can be further-purifiedby recrystallization from Skellysolve B hexanes-acetone; Reaction ofthesaid 9( l1-)'-oxido compound in methylene chloride solution with aqueoushydrogen-fluorideor hydrogen fluoride gasin the presence oftetrahydrofuran at room temperature is productive of6,9a,2l-trifluorol118,17tx-dihydroxy-4-pregnene-3,20-dione. Substitutionof aqueous hydrogen chloride for the hydrogen fluoride above yields 6,21dlfll10lO-9a-Chl01'O-l lB,17a-dihydroxy-4-pregnene-3,20-dione. Ifdesired, either the 9a-fluoro or chloro product can be oxidized, forexample, with N-bromoacetamide in pyridine solution to give6,9a,2l-trifiuoro-l7othydroxy-4-pregnene-3,l1,20-trione or thecorresponding 9m-chloro compound.

The steps of the foregoing process for the preparation of the t-ha1Osteroids can be inverted without departing 5 V tomarily employed foracylating hydrocortisone, for example, by reaction of the appropriate21-hydroxy steroid with the anhydride or acid halide of an organiccarboxylic acid containingfrom one to twelve carbon atoms, inclusive,under conventional esterifying conditions. The said 2l-acyloxy steroidcan be dehydrated as by reaction with N-bromoacetamide and anhydroussulfur dioxide in pyridine and the 9u,l1fi-bromohydrin formed bytreatment with N-bromoacetamide in an acidic aqueous organic solution.The 9(11)-oxido group can then be introduced by reaction of thebromohydrin with potassium acetate in acetone. Fluorination of theresulting compound, followed by hydrolysis, as with potassiumbicarbonate, produces 6,9a difluoro 11B,17a,21 trihydroxy 4pregnene-3,20-dione, which can be fluo'rinated at the 21-position by thesteps and methods earlier described.

In the foregoing processes, it should be understood that thecorresponding 6/3 halo epimer can be utilized at any stage and thea-epimer obtained at appropriate inter mediate stages by treatment ofthe 6p-compoundin an organic solvent such as chloroform, at temperaturesof zero degrees centigrade or slightly lower, with an anhy drous mineralacid, such as hydrochloric acid, in the presence of alcohol. Suchtemperatures should be main tained throughout the period of addition ofthe acid. The reaction mixture can then be washed with successiveportions of dilute alkali and water and evaporated under reducedpressure to obtain the 6a-epimer in high yield.

The following preparations and examples are illustrative of the processand products of the present invention but are not to be construed aslimiting.

' PREPARATION 1 3-ethylene glycol ketal of methyl3,11-dilceto5a,6a-oxido- 17(20)-[cis]-pregnen-21-oate To a solution offivegrams of the B-ethylene glycol ketal of methyl3,11-diketo-4,l7(20)-[cisl-pregnadien-Zloate, prepared in the mannerdescribed in U. S. Patent 2,707,184, in 100 milliliters of chloroformwas added a chilled solution of 1.9 grams of perbenzoic acid dissolvedin 31.5 milliliters of chloroform. The solution was maintained at aboutfour degrees centigrade for24 hours, and then at room temperature for 72hours. The solution was washed with a five percent aqueous solution ofsodium PREPARATION 2 Methyl 3,11-diket-5a, 6/3-dihydroxy-1 7 (20-allopregneri- 21 ame and methyl 3,11-diketo-a-hydroxy-6,B-flu0ro-17(20) -a llopregnen-21-oate To a solution of 1.73 grams of 3-ethyleneglycol ketal of methyl 3,11-diketo-5a,6a-oxido-l7(20)-[cisl-pregnen-2l-oate in sixteen milliliters of methylene chloride was added sixmilliliters of 48 percent hydrofluoric acid. The

heterogeneous mixture was stirred for two hours, made slightly basicwith 300 milliliters of five percent sodium bicarbonate solution, andextracted with methylene chloride. The-extract was washed, dried, andevaporated to dryness to give 1.62 grams of crude solid. Purification bychromatography gave two fractions: A, 481' millichloride plus ten andtwenty percent acetone. Crystallization of fraction A fromacetone-Skellysolve B hexanes gave 390 milligrams of methyl3,11-diketo-5a-hydroxy- 618-fluoro-l7(20)-allopregnen-21-oate, meltingpoint 254 to 260. degrees centigrade. The analytical sample melted at260 to 263 degrees centigrade.

Analysis.Calculated for C H O F: F, 4.84. Found: F, 4.47.

Fraction B on crystallization from acetone-Skellysolve B hexanes gave470 milligrams of methyl 3,11-diketo- ,6B dihydroxy 17(20) allopregnen21 oate, melting point 235 to 245 degrees centigrade. sample melted at245 to 248 degrees centigrade.

Analysis.-Calculated for C H O C, 67.67; H, 7.74. Found: C, 67.91; H,7.62.

PREPARATION 3 Methyl 3,1 1-diket0-5a-hydroxy-6fi-Yuor0-1 7 (20) Iallopregnen-Z] -oate S-ethy lene ketal A mixture of 1.9 grams of methyl3,11-diketo-5u-hy droxy 6 9- fluoro 17(20) allopregnen 21 oate, 59milligrams of p-toluenesulfonic acid monohydrate and 31 milliliters ofdistilled ethylene glycol was added to 800 milliliters of benzene. Themixture was stirred and refluxed for two hours, with the condensatepassing through a water trap to remove the water. After reflux themixture was cooled, washed with water and evaporated to dryness to givea crude solid which on recrystallization from acetone-Skellysolve Bhexanes gave 1.96 grams of methyl 3,11 diketo 5oz hydroxy 6,6 fluoro17(20)- allopregnen-Zl-oate 3-ethylene ketal, melting point 170 to 173degrees centigrade.

Following the above procedure, substituting other dihydric alcohols forethylene glycol, for example, 1,2-propylene glycol, 2,3-butanediol,1,3-butanediol and 2,3-pentanediol, is productive of the respective3-alkylene ketals of methyl3,11-diketo-5u-hydroxy-6,B-fiuoro-17(20)-allopregnen-Zl-oate.

PREPARATION 4 5 0a,] 118,21-trihydr0xy-6;8-fluor0-1 7(20) -allopregnen-3-0ne 3-ethylene ketal To a solution of 1.96 grams of methyl3,1l-diketo-5ahydroxy-fi-fiuoro- 17 20 -allopregnen-2 l-oate 3-ethyleneketal in 850 milliliters of anhydrous ether was added 3.7 grams oflithium aluminum hydride. The mixture was 1 stirred for a period of onehour, and 200 milliliters of acetone, and B, 921 milligrams eluted withmethylene water was added slowly, the ether phase separating. Theaqueous phase was extracted with ethyl acetate and the extracts added tothe ether phase. The combined etherethyl acetate solution was washedwith water, dried and evaporated to dryness under reduced pressure. Thecrude solid residue was crystallized from acetone-Skellysolve B hexanesto give 1.30 grams of 5u,1l}3,21-trihydroxy-6fifluoro 17(20)-a1lopregnen 3 one 3 ethylene ketal, melting point 197 to 205 degreescentigrade. An additional 226 milligrams was obtained from the motherliquor, melting point 175 to 185 degrees centigrade.

PREPARATION 5 5 01,1 1 fi-dihydroxy-6 B-fluoro-21 -acet0xy-1 7(20)all0pregnen-3-0ne 3-ethylene ketal The acetate was prepared by allowing0.87 gram of 5a,1lfl,2l trihydroxy 65 fluoro 17(20) allopregnen- 3-one3-ethylene ketal to stand overnight in ten milliliters of aceticanhydride and ten milliliters of pyridine. The solution was then pouredinto ice water to give 0.92 gram of 50,11B dihydroxy 6/3 fluoro 21acetoxy 17(20)- allopregnen-B-one 3-ethylene ketal, melting point todegrees centigrade, which on recrystallization fromacetone-Skellysolve'B hexanes gave 0.77 gram, melting point 149 to 153degrees centigrade.

The analytical Similarly, other 2l-organic carboxylic esters of5a,11B,21 trihydroxy 6;? fluoro 17(20) allopregnen- 3-one 3-ethyleneketals can be prepared wherein the 21- acyloxy group is formyloxy,propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy,oetanoyloxy, benzoyloxy, phenylacetoxy, or the like, by contacting504,116,21 trihydroxy 6B fluoro 17(20) pregnen- 3 -one 3 ethylene ketalwith the appropriate acylating agent, e. g., the anhydride or acidhalide of the selected acid in'a solvent such as benzene, toluene,acetic acid, or the like. A convenient method of preparing the21-formyloxy ester consists in contacting 5a,11fi,21-trihydroxy- 6/3fluoro 17(20) pregnen 3 one 3 ethylene ketal with formic acid in thepresence of paratoluenesulfonic acid.

PREPARATION 6 To a solution of 0.77 gram of 5a,1l/3-dihydroxy-6[3-fiuoro 21 acetoxy 17(20) allopregnen 3 one 3- ethylene ketal in 35milliliters of tertiary 'butyl alcohol was added one milliliter ofpyridine, 1.9 milliliters of N- methylmorpholine oxide peroxidesolution, and 13.1 milligrams of osmium tetroxide (9.1 milliliters oftertiary butyl alcohol solution containing 1.44 milligrams of osmiumtetroxide per milliliter). The solution was stirred for a period of 2.5hours and fifteen milliliters of five percent sodium hydrosulfite wasadded. Stirring was continued for an additional ten minutes, at whichtime 0.7 gram of finely ground synthetic magnesium silicate was mixedinto the solution for a period of twenty minutes and then re-PREPARATION 7 5 01,1 1 5,1 7 a-trihydrxy-6B-fluoro-Zl-acetoxyallopregnane- 3 ,ZO-dione A solution of 0.4-7 gram ofm,l1fi,l7a-trihydro-Xy-6B- fluoro-Z1-acetoxyallopregnane-3,20-dione3-ethylene .lcetal in 35 milliliters of acetone and four milliliters of1 N sulfuric acid solution was gently boiled on a steam bath for tenminutes, cooled and neutralized with dilute sodium bicarbonate solution.Addition of water followed by cooling gave 0.33 gram of 5,11B,17u-tri'hydroxy-6fi-fluoro- 2l-acetoxyallopregnane-3,ZO-dione,melting point 230 to 240 degrees centigrade.

PREPARATION 8 A solution of 100 milligrams of 5a,11,B,l7a-trihydroxy-6fl-fiuoro-2l-acetoxyallopregnane-3,ZO-dione in 4.9 milliliters ofacetic acid and 0.1 milliliter of water was retluxed for a period of onehour, cooled, diluted with fifty milliliters of Water and evaporated todryness under reduced pressure. The residue was chromatographed oversynthetic magnesium silicate to give one fraction (77 milligrams) elutedwith methylene chloride plus ten percent acetone. Crystallization fromacetone-Skellysolve 'B'hexanes gave 38 milligrams of6B-fiuoro-11B,17adihydroxy-21-acetoxy-4-pregnene-3,ZO-dione (6 8fluorohydrocortisone acetate), melting point 210 to 218 degreescentigrade. Infrared data and ultraviolet data were in agreement withthe structure.

8 PREPARATION 9 A solution of 0.132 gram of6{3fiuoro-11fl,17a-dihydroXy-21-acetoxy-4-pregnene-3,20-dione in twelvemilliliters of chloroform-and 0.1 milliliter of absolute alcohol wascooled to minus ten degrees centigrade in an ice-salt bath. A- stream ofanhydrous hydrochloric acid was gently bubbled through the solution for2.5 hours, during which period the temperature was maintained betweenminus five and minus fifteen degrees centigrade. The solution was thendiluted with 25 milliliters of chloroform, washed with dilute aqueoussodium bicarbonate solution, dried over anhydrous sodium sulfate, andevaporated to dryness under reduced pressure at sixty degreescentigrade. Crystallization of the residue from acetone- Skellysolve Bhexanes' gave 42 milligrams of the isomerized product,6m-fiuoro-1l5,17a-dihydroxy-21-acetoxy- 4-pregnene-3,20-dione, whichmelted at 203 to 210 degrees centigrade.

PREPARATION 10 A solution of 1.1 grams of6a-flu0ro11,8,17a-dihydroxy-Zl-acetoxy-4-pregnene-3,ZO-dione, one gramof potassium bicarbonate, 100 milliliters of methanol and fifteenmilliliters of water were mixed together and purged with nitrogen'toremove dissolved oxygen While stirring at 25 degrees centigrade for fourhours. The solution was then neutralized by addition of acetic acid anddistilled under vacuum to remove the methanol. The residue was extractedwith 100 milliliters of methylene dichloride, and the extract was driedover sodium sulfate and passed through a column containing eighty gramsof synthetic magnesium silicate. The fraction eluted with Skellysolve Bhexanes plus twenty and thirty percent acetone weighed 770 milligrams,representing a yield of 77.5 percent. Recrystallization of a portion ofthis crude product from ethyl acetate-Skellysolve B hexanes gavecrystals of 6a-fiuorohydrocortisone, melting at 192 to 195 degreescentigrade.

PREPARATION l1 6 fl-flizoro-J 7 0;,21 -dihydroxy-4-pregnene-3,1 1,20-frione (6 ,B-fluorocortisone) To a solution of 0.5 gram of6/S-fiuoro-11B,l7a,2ltrihydroxyl-pregnene-3,20-dione, prepared asdescribed in Preparation 8, and one milliliter of pyridine in 35milliliters of tertiary'butyl' alcohol was added 250 milligramsof'N-bromoacetamide. After maintaining at room temperature for sixteenhours, the reaction mixture was diluted with 25 milliliters of watercontaining 250 milligrams of sodium sulfite and concentrated to abouttwenty milliliters, at which point precipitation occurred. The thusobtained precipitate was collected on a filter and recrystallized threetimes from ethyl acetate and Skellysolve B hexanes to 'give6,8-fiuoro-17a,21-dihydroxy 4- pregnene-3, 1 1,20-trione.

Substitution of the corresponding 6a-epimer for the starting materialabove is productive of6oz-fl110I0-17u,2ldihydroxy-4-pregnene-3,11,20-trione. Alternatively,the 6m-epirner can be obtained from the corresponding 65- product by theprocedure of Preparation 9.

EXAMPLE 1 6a-flu0'r0-1I{3,I7&2!-trihydr0xy-4-pregnerte-3,20- dione 21-methanesulf0nate (II) To a solution of 770 milligrams of crudeGot-fluoro- 11p ,l704,2l-trihydroxy-4-pregnene-3,ZO-dione (I) in ten 9milliliters of pyridine previously cooled to zero to five degreescentigrade was added 0.7 milliliter of methanesulfonyl chloride. Thereaction mixture was stirred in an ice-water bath for four hours.Dilution with 100 milliliters of five percent hydrochloric acidprecipitated the crystalline mesylate (II). The product, afterfiltration, weighed 900 milligrams and melted at 189 to 192 degrees(with decomposition). Infrared analysis in mineral oil mull showedadsorptions as follows: 3560, 3420 centimeters- (OH); 1725 centimeters--(20-ketone); 1655 centimeters- (A -3-ketone); 1640, 1617 centimeterr(C=C); 1350, 1200, 1170 centimeters- (OSO EXAMPLE 2 611,21 -difluoro-I 15,1 70: dihydroxy-4-pregnene-3,ZO-a'ione(612,21-diflur0-21-des0xyhydr0c0rtis0ne) (III) A mixture of 200milligrams of 6a-fluoro-11/3,17adihydroxy-4-pregnene-3,20-dione 21methanesulfonate (II) and 100 milligrams of potassium fluoride in twomilliliters of dimethylsulfoxide was heated on a steam bath forseventeen hours. The reaction mixture was diluted with fifty millilitersof methylene chloride and washed three times with ten milliliters ofwater. After drying over sodium sulfate, the methylene chloride solutionwas passed over a column of ten grams of synthetic magnesium silicate.Elution with Skellysolve B hexanes plus nine percent acetone (fourfractions of twenty milliliters each) gave 28 milligrams of crudecrystals identified by infrared data as 6oz-fluoro-11,B-hydroxy-17,21-epoxy-4-pregnen-3-one. The infrared adsorption maximums in mineral oilmull were as follows: 3410 centimeters- (OH); 1807 centimeters" (C=O,4-membered ring); 1660 centimeters" (A -3-keto); 1625 centimeters (C=C).This compound possesses pharmacological properties similar to those ofCompounds III and V, though to a modified degree.

Further elution with Skellysolve B hexanes plus twelve and fifteenpercent acetone yielded 45 milligrams of 60:,21-diflllOIO-l 1B,17ondihydroxy-4-pregnene-3,20-dionc (III), which on recrystallization fromethyl acetate- Skellysolve B hexanes gave 29 milligrams of product(III), melting point 226 to 230 degrees centigrade. Infrared adsorptionshowed the following maximums: 3600, 3540, 3360 centimeters" (OH); 1722centimeters- (20-ketone); 1653 centimeters- (A -3-ketone); 1625centimeters (C=C).

EXAMPLE 3 611,21 difluoro 17a. hydroxy 4 pregnene 3,11,20- trione(6a,21-difluora-21-desoxycortisone) (V) A solution is preparedcontaining 0.5 gram of 6u,21-difluoro-l1B,17a-dihydroxy-4-pregnene-3,20-dione, 0.15 gram of chromiumtrioxide, ten milliliters of glacial acetic acid and one-half milliliterof water. This mixture is stirred and maintained at room temperature foreight hours. Thereafter the mixture is poured into fifty milliliters ofice water, neutralized by the addition of dilute sodium hydroxide, andthe thus obtained precipitate collected on a filter and recrystallizedthree times from ethyl acetate and Skellysolve B hexanes to give 6a,21difluoro 17a hydroxy 4 pregnene 3,11,20- trione (V).

Alternatively, 6a,2l-difluoro-l7a-hydroxy-4-pregnene- 3,11,20-trione (V)can be produced by employing 6afluoro-l7oz-hydroxy4-pregnene-3,l1,20-trione as the starting material in Example 1 andfollowing the procedures of Examples 1 and 2.

EXAMPLE 4 60:,21 difluoro 115,170; dihydroxy 4 pregnene- 3,20 dione(60:,21 difluoro 21 desoxyhydrocontisone) (IV) and 60,21 difluoro 17ahydroxy 4- pregnene 3,11,20 trione (612,21 difluoro 21- desoxycortisone)(V) In the same manner as shown in Example 1, treating 6oz fiuoro 113,17e,21 trihydroxy 4 pregnene 3,20- dione with methanesulfonyl chloridein pyridine solution yields 60: fiuoro 11fl,17a,21 trihydroxy 4pregnene- 3,20-dione 21-methanesulfonate. Refluxing the said 21-methanesulfonate with potassium iodide in acetone solution gives6a-fluoro-l1/3,17m-dihydroxy-2l-iodo-4-pregnene-3,20-dione. Reacting thethus obtained 6a-fluorol1,8,17a-dihydroxy-21-iod'o-4-pregnene-3,20-dionein ace tonitrile solution with aqueous silver fluoride solution produces6u,21-clifluoro-11B,17oc-dihydroxy-4-pregnene-3,20- dione (IV).

Substitution of Goa-fluoro-17a,21-dihydroxy-4-pregnene- 3,11,20-tri0neas the starting material in the foregoing reactions of Example 4 isproductive of 6u,21-difluorol7a hydroxy 4 pregnene 3,11,20 trione.Alternatively, 611,21 difluoro 115,170: dihydroxy 4- pregnene-3,20-dionccan be oxidized to 6a,21-difluorol7e-hydroxy-4-prcgnene-3,11,20-trione(V), as indicated in Example 3.

EXAMPLE 5 6fl-epim ers Substituting 6B-flu0rohydrocortisone for thestarting material in Example 1 and maintaining the reaction conditionsnear neutral, 6/3-epimers, such as 6[3,2l-difluoro-1118,17a-dihydroxy-4-pregnene-3,20-dione and6,8,21-difluoro-17u-hydroxy-4-pregnene-3,11,20-trione, are producedwhich can be isolated from the reaction mixture. The thus obtainedGB-epimers yield the 6a-epimers by treatment, at temperatures of zerodegrees centigrade or slightly lower and in an organic solvent such aschloroform, with an anhydrous mineral acid, such as hydrochloric acid,in the presence of alcohol. The lower temperature should be maintainedthroughout the period of acid addition. Purification by washing withsuccessive portions of dilute alkali followed by evaporation underreduced pressure gives the fiu-epimer in high yield.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art. The invention is therefore to be limited only by the scope ofthe appended claims.

We claim:

1. A compound selected from the group consisting of6,21-difluoro-2l-desoxyhydrocortisone and 6,21-difluoro-2l-clesoxycortisone.

2. A compound selected from the group consisting of 6u,21-difluoro-2l-desoxyhydrocortisone and 6a,21-difluoro-21-desoxycortisone.

3. 6a,21-difluoro-2l-desoxyhydrocortisone.

4. 601,21difluoro-2l-desoxycortisone.

References Cited in the file of this patent UNITED STATES PATENTS HerrNov. 19, 1957 Nussbaum Nov. 26, 1957 OTHER REFERENCES

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF6,21-DIFLUORO-21-DESOXYHYDROCORTISONE AND6,21-DIFLUORO21-DESOXYCORTISONE.